Use of 3,4-methylenedioxymethamphetamine (MDMA, or "Ecstasy") is a significant health problem in the United States. High doses of MDMA damage the serotonergic system in adult animals, and similar consequences may occur in heavy Ecstasy users. Many studies have also found an association between Ecstasy use and cognitive deficits, heightened anxiety, and increased impulsivity. However, interpretation of these findings is confounded by the fact that most heavy Ecstasy users also regularly use cannabis, thus raising important questions as to the source of the cognitive and neuropsychiatric abnormalities observed in Ecstasy/cannabis co-users. Because Ecstasy use typically begins during adolescence and commonly occurs intermittently (e.g., on weekends at dances), our laboratory has developed a novel rat model of intermittent adolescent MDMA exposure. Animals treated using this model show a relatively modest serotonergic neurotoxicity (compared to high-dose binge regimens) that resembles the results obtained from neuroimaging studies of the serotonergic system in Ecstasy users. In subsequent behavioral testing, the MDMA-treated animals showed memory impairment as well as other effects that may be indicative of increased impulsivity. The proposed studies represent a pilot project designed to investigate the separate and combined behavioral and neurotoxic effects of MDMA and ?9-tetrahydrocannabinol (THC;the main psychoactive ingredient in cannabis) given repeatedly to adolescent male and female rats. Beginning at 1 week following the end of the dosing period, we will test drug-treated and control animals for their performance in several tests of spatial and non-spatial learning and memory, or for their behavioral and adrenocortical responses in several tests of anxiety or impulsivity. The effects of the treatments on regional brain serotonin transporter expression will be ascertained to determine possible relationships between behavioral and hormonal responses and serotonergic neurotoxicity in key brain areas involved in learning, memory, and anxiety. These studies will provide important new information on the separate and combined effects of MDMA and THC exposure during adolescence, thereby helping to resolve a controversial issue that has continued to plague the clinical Ecstasy literature. PUBLIC HEALTH RELEVANCE: Many young people regularly use the drug "Ecstasy", and there is scientific evidence that such use has adverse effects on the users'brain function and behavior. Because most Ecstasy users also smoke marijuana, researchers have had difficulty determining whether some of the negative consequences of Ecstasy, especially those involving memory deficits, might instead be related to repeated marijuana exposure. The proposed research will help answer this important problem by using controlled studies of experimental animals to determine the influence of these two drugs separately or together on learning, memory, and anxiety.